Genetic basis of malignant melanoma is poorly understood. Progress in our understanding of the pathogenesis of malignant melanoma and in the design of therapeutic modalities has been significantly hampered by the lack of a bona fide animal model. In this proposed study, transgenic and knockout mouse technology will be utilized to construct a mouse model for malignant melanoma. Commonly encountered melanoma-associated genetic lesions will be analyzed in vitro to dissect their molecular functions and their causal roles in disease will be validated in vivo. Specifically, I will focus on the differential roles of p15 INK4b, P16INK4a and p19ARF as well as activated H-rasva112 in development of malignant melanoma. My working hypothesis is that loss of both gene products of the INK4a gene, (namely p16INK4a and p19ARF), are important, but not sufficient, in development of malignant melanoma, that p15INK4b does not play a key role in melanoma pathogenesis, and that additional genetic events such as RAS activation may be necessary to achieve full malignant transformation of melanocytes.